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Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Schumacher FR 1 , Al Olama AA 2 , Berndt SI 3 , Benlloch S 4 , Ahmed M 5 , Saunders EJ 5 Show all authors , Dadaev T 5 , Leongamornlert D 5 , Anokian E 5 , Cieza-Borrella C 5 , Goh C 5 , Brook MN 5 , Sheng X 6 , Fachal L 7 , Dennis J 4 , Tyrer J 4 , Muir K 8 , Lophatananon A 8 , Stevens VL 9 , Gapstur SM 9 , Carter BD 9 , Tangen CM 10 , Goodman PJ 10 , Thompson IM 11 , Batra J 12 , Chambers S 13 , Moya L 12 , Clements J 12 , Horvath L 14 , Tilley W 15 , Risbridger GP 16 , Gronberg H 17 , Aly M 18 , Nordström T 17 , Pharoah P 4 , Pashayan N 19 , Schleutker J 20 , Tammela TLJ 21 , Sipeky C 20 , Auvinen A 22 , Albanes D 3 , Weinstein S 3 , Wolk A 23 , Håkansson N 23 , West CML 24 , Dunning AM 19 , Burnet N 25 , Mucci LA 26 , Giovannucci E 26 , Andriole GL 27 , Cussenot O 28 , Cancel-Tassin G 28 , Koutros S 3 , Beane Freeman LE 3 , Sorensen KD 29 , Orntoft TF 29 , Borre M 30 , Maehle L 31 , Grindedal EM 31 , Neal DE 32 , Donovan JL 33 , Hamdy FC 34 , Martin RM 33 , Travis RC 35 , Key TJ 35 , Hamilton RJ 36 , Fleshner NE 36 , Finelli A 37 , Ingles SA 6 , Stern MC 6 , Rosenstein BS 38 , Kerns SL 39 , Ostrer H 40 , Lu YJ 41 , Zhang HW 42 , Feng N 43 , Mao X 41 , Guo X 44 , Wang G 45 , Sun Z 46 , Giles GG 47 , Southey MC 48 , MacInnis RJ 47 , FitzGerald LM 47 , Kibel AS 49 , Drake BF 27 , Vega A 7 , Gómez-Caamaño A 50 , Szulkin R 51 , Eklund M 17 , Kogevinas M 52 , Llorca J 53 , Castaño-Vinyals G 52 , Penney KL 54 , Stampfer M 54 , Park JY 55 , Sellers TA 55 , Lin HY 56 , Stanford JL 57 , Cybulski C 58 , Wokolorczyk D 58 , Lubinski J 58 , Ostrander EA 59 , Geybels MS 57 , Nordestgaard BG 60 , Nielsen SF 60 , Weischer M 61 , Bisbjerg R 62 , Røder MA 63 , Iversen P 63 , Brenner H 64 , Cuk K 64 , Holleczek B 65 , Maier C 66 , Luedeke M 66 , Schnoeller T 67 , Kim J 68 , Logothetis CJ 68 , John EM 69 , Teixeira MR 70 , Paulo P 70 , Cardoso M 70 , Neuhausen SL 71 , Steele L 71 , Ding YC 71 , De Ruyck K 72 , De Meerleer G 72 , Ost P 73 , Razack A 74 , Lim J 74 , Teo SH 75 , Lin DW 57 , Newcomb LF 57 , Lessel D 76 , Gamulin M 77 , Kulis T 78 , Kaneva R 79 , Usmani N 80 , Singhal S 80 , Slavov C 81 , Mitev V 79 , Parliament M 80 , Claessens F 82 , Joniau S 83 , Van den Broeck T 82 , Larkin S 84 , Townsend PA 85 , Aukim-Hastie C 86 , Gago-Dominguez M 87 , Castelao JE 88 , Martinez ME 89 , Roobol MJ 90 , Jenster G 90 , van Schaik RHN 91 , Menegaux F 92 , Truong T 92 , Koudou YA 92 , Xu J 93 , Khaw KT 94 , Cannon-Albright L 95 , Pandha H 86 , Michael A 86 , Thibodeau SN 96 , McDonnell SK 97 , Schaid DJ 97 , Lindstrom S 98 , Turman C 99 , Ma J 54 , Hunter DJ 99 , Riboli E 100 , Siddiq A 101 , Canzian F 102 , Kolonel LN 103 , Le Marchand L 103 , Hoover RN 3 , Machiela MJ 3 , Cui Z 104 , Kraft P 99 , Amos CI 105 , Conti DV 6 , Easton DF 4 , Wiklund F 17 , Chanock SJ 3 , Henderson BE 6 , Kote-Jarai Z 5 , Haiman CA 6 , Eeles RA 106 , Profile Study , Australian Prostate Cancer BioResource (APCB) , IMPACT Study , Canary PASS Investigators , Breast and Prostate Cancer Cohort Consortium (BPC3) , PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium , Cancer of the Prostate in Sweden (CAPS) , Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS) , Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium

Affiliations 

  • 1 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. frs2@case.edu
  • 2 Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK. aa461@medschl.cam.ac.uk
  • 3 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
  • 4 Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
  • 5 Institute of Cancer Research, London, UK
  • 6 Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
  • 7 Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain
  • 8 Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester, UK
  • 9 Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
  • 10 SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • 11 CHRISTUS Santa Rosa Hospital-Medical Center, San Antonio, TX, USA
  • 12 Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia
  • 13 Menzies Health Institute of Queensland, Griffith University, Nathan, Queensland, Australia
  • 14 Chris O'Brien Lifehouse (COBLH), Camperdown, New South Wales, Australia
  • 15 Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, South Australia, Australia
  • 16 Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Program, Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia
  • 17 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 18 Department of Urology, Karolinska University Hospital, Stockholm, Sweden
  • 19 Department of Oncology, Centre for Cancer Genetic Epidemiology, Strangeways Laboratory, University of Cambridge, Cambridge, UK
  • 20 Institute of Biomedicine, University of Turku, Turku, Finland
  • 21 Department of Urology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
  • 22 Department of Epidemiology, School of Health Sciences, University of Tampere, Tampere, Finland
  • 23 Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  • 24 Division of Cancer Sciences, Manchester Cancer Research Centre, Manchester Academic Health Science Centre and Christie NHS Foundation Trust, University of Manchester, Manchester, UK
  • 25 Department of Oncology, Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge, Cambridge, UK
  • 26 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
  • 27 Washington University School of Medicine, St. Louis, MO, USA
  • 28 UPMC Sorbonne Universités, GRC no. 5 ONCOTYPE-URO, Tenon Hospital, Paris, France
  • 29 Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
  • 30 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
  • 31 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  • 32 Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
  • 33 School of Social and Community Medicine, University of Bristol, Bristol, UK
  • 34 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK, Faculty of Medical Science, John Radcliffe Hospital, University of Oxford, Oxford, UK
  • 35 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
  • 36 Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 37 Division of Urology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 38 Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • 39 Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA
  • 40 Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
  • 41 Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
  • 42 Second Military Medical University, Shanghai, China
  • 43 Wuxi Second Hospital, Nanjing Medical University, Wuxi, China
  • 44 Department of Urology, First Affiliated Hospital, Chongqing Medical University, Chongqing, China
  • 45 Department of Urology, Zhongshan Hospital, Fudan University Medical College, Shanghai, China
  • 46 People's Hospital of Liaoning Province, People's Hospital of China Medical University, Shenyang, China
  • 47 Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia
  • 48 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
  • 49 Division of Urologic Surgery, Brigham and Womens Hospital, Boston, MA, USA
  • 50 Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
  • 51 Division of Family Medicine, Department of Neurobiology, Care Science and Society, Karolinska, Institutet, Huddinge, Sweden
  • 52 ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
  • 53 CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
  • 54 Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
  • 55 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
  • 56 Biostatistics Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
  • 57 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • 58 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 59 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • 60 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • 61 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 62 Department of Urology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 63 Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 64 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 65 Saarland Cancer Registry, Saarbrücken, Germany
  • 66 Institute for Human Genetics, University Hospital Ulm, Ulm, Germany
  • 67 Department of Urology, University Hospital Ulm, Ulm, Germany
  • 68 Department of Genitourinary Medical Oncology, University of Texas-MD Anderson Cancer Center, Houston, TX, USA
  • 69 Cancer Prevention Institute of California, Fremont, CA, USA
  • 70 Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal
  • 71 Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA
  • 72 Faculty of Medicine and Health Sciences, Basic Medical Sciences, Ghent University, Ghent, Belgium
  • 73 Department of Radiotherapy, Ghent University Hospital, Ghent, Belgium
  • 74 Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 75 Cancer Research Malaysia (CRM), Outpatient Centre, Subang Jaya Medical Centre, Selangor, Malaysia
  • 76 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 77 Department of Oncology, Division of Medical Oncology, Urogenital Unit, University Hospital Centre Zagreb, Zagreb, Croatia
  • 78 Department of Urology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia
  • 79 Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, Bulgaria
  • 80 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
  • 81 Department of Urology and Alexandrovska University Hospital, Medical University of Sofia, Sofia, Bulgaria
  • 82 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
  • 83 Department of Urology, University Hospitals Leuven, Leuven, Belgium
  • 84 University of Southampton, Southampton General Hospital, Southampton, UK
  • 85 Division of Cancer Sciences, Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Center, NIHR Manchester Biomedical Research Centre, Health Innovation Manchester, University of Manchester, Manchester, UK
  • 86 University of Surrey, Guildford, Surrey, UK
  • 87 Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saúde, SERGAS, Santiago de Compostela, Spain
  • 88 Genetic Oncology Unit, CHUVI Hospital, Instituto de Investigación Biomédica Galicia Sur (IISGS), Complexo Hospitalario Universitario de Vigo, Vigo, Spain
  • 89 Department of Family Medicine and Public Health, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
  • 90 Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 91 Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 92 Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  • 93 Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA
  • 94 Clinical Gerontology Unit, University of Cambridge, Cambridge, UK
  • 95 Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
  • 96 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
  • 97 Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
  • 98 Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
  • 99 Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
  • 100 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
  • 101 Genomics England, Queen Mary University of London, London, UK
  • 102 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 103 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
  • 104 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
  • 105 Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
  • 106 Institute of Cancer Research, London, UK. ros.eeles@icr.ac.uk
Nat Genet, 2018 07;50(7):928-936.
PMID: 29892016 DOI: 10.1038/s41588-018-0142-8

Abstract

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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